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Study: Topical Tamoxifen Gel Effective in Breast Cancer, With Fewer Side Effects Than Oral Formulation

Blood levels more than fivefold lower in gel-treated patients

A breakdown product of tamoxifen, 4-OHT, applied as a gel formulation on the breasts of women with ductal carcinoma in situ (DCIS), was as effective in reducing cell proliferation as oral tamoxifen, with fewer side effects, according to a new study published in Clinical Cancer Research.

“In this study, we have shown that the gel application of 4-OHT to the skin resulted in high drug levels in the breast but low drugs levels in the circulation. This would maintain the effectiveness of the drug, but minimize the side effects,” said lead investigator Seema A. Khan, MD.

“Oral tamoxifen is used by some women at high risk for breast cancer to prevent the development of the disease, and our data suggest that gel application of tamoxifen could replace this approach, thus encouraging more women to adhere to preventive therapy,” she added.

Khan and her colleagues conducted a randomized, double-blind, placebo-controlled phase II clinical trial to compare the effects of 4-OHT gel applied on the breasts with those of tamoxifen taken orally. They found that after 6 to 10 weeks of gel application, the reduction in a marker of cell proliferation (Ki-67) in breast tissue was comparable with that of oral tamoxifen taken for a similar period of time. Blood levels of the drug were much lower when applied as a gel, compared with oral tamoxifen, and this reduced hormonal side effects and blood clotting, which commonly occur among patients treated with oral tamoxifen.

The researchers randomly assigned 26 women (aged 45 to 86 years) with a diagnosis of estrogen receptor-positive DCIS to either the 4-OHT gel arm or the oral tamoxifen arm. All patients provided a baseline blood sample and completed the Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire. For 6 to 10 weeks prior to surgery, patients in the gel arm applied 1 mL of the gel (containing 2 mg of 4-HT) to the skin of each breast every morning. Patients from the oral tamoxifen arm took a 20-mg tamoxifen capsule every day.

The researchers found that equal amounts of 4-OHT were present in the breast tissue of patients in both the gel and oral tamoxifen arms (5.8 ng/g vs. 5.4 ng/g, respectively) collected during surgery, but the levels of 4-OHT in the blood of patients in the gel arm were 5.5-fold lower than they were in the blood of those in the oral tamoxifen arm (0.2 ng/mL vs. 1.1 ng/mL, respectively).

The substantial reduction in the levels of 4-OHT in the blood of patients who used the gel correlated with a reduction in factors that cause blood clots.

“Tamoxifen has to be broken down by the liver to its active components, which include 4-OHT. In this process, harmful side effects can also arise, such as the activation of proteins that cause blood clots. Because the liver metabolism step is eliminated when the 4-OHT gel is directly applied to breast skin, the harmful effect of increasing the risk for blood clots should also be eliminated,” Khan explained.

Based on the BESS questionnaire, however, patients in the gel arm showed no significant improvement in vaginal symptoms, gastrointestinal symptoms, or hot flashes and sweats compared with those in the oral tamoxifen arm.

Source: AACR; July 15, 2014.

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